Abstract 3450: Discovery and preclinical study of novel BTK degrader HZ-Q1070
Authors: Xingguo Liu, Yubo Zhou, Yizhe Wu, Xiaomin Luo, Jiangfeng Xie, Xinxin Jin, Jia Li, Xinglu Zhou
Journal: Cancer Research (2023)

Abstract Introduction: Bruton's tyrosine kinase (BTK) is a clinical validated target for B cell lymphoma and autoimmune diseases. However, acquired resistance, which is the result of BTK C481S mutation, has been observed in patients. So reversible BTK inhibitors are developed to overcome acquired resistance of covalent BTK inhibitors. In order to achieve adequate efficacy, reversible BTK inhibitors require much higher exposure which may lead to higher risk of adverse effect. Proteolysis-targeting chimera (PROTAC) is a novel drug discovery strategy and achieve sustained target degradation though a catalytic mechanism of action. Comparing with traditional small molecule inhibitor, PROTAC has shown great advantages in overcoming acquired resistance, since potent and sustained active site occupation is no longer required. Here, we have identified a novel BTK-PROTAC HZ-Q1070 based on our DaTProD® platform, which is set up to promote the druggability research of PROTAC. After a series of evaluations, HZ-Q1070 has been validated as a promising pre-clinical candidate for further clinical development. Results: 1. HZ-Q1070 can effectively degrade BTK in cancer cell lines with DC50 &amp;lt; 0.05 nM. In vitro cancer cell growth inhibition assay, it completely suppressed the cell proliferation of a panel of lymphoma cell lines with IC50 &amp;lt; 0.05 nM, such as Mino, OCI-ly10 and TMD8. 2. At the same time, HZ-Q1070 catalyzes the mutated BTK degradation (C481S/C481Y/C481F/T474M) and potently inhibits growth of BTK inhibitor-resistant tumor cell lines. 3. In proteomic analysis assay, HZ-Q1070 can selectively degrade BTK. 4. HZ-Q1070 has been engineered to avoid Aiolos and Ikaros degradation and therefore does not show IMiD activity. 5. Mechanistic investigation of indicates that HZ-Q1070 can function through the ubiquitin-proteasome system (UPS). 6. In the PK/PD experiments, HZ-Q1070 shows excellent pharmacokinetic properties and BTK degradation activity in vivo. 7. HZ-Q1070 demonstrates robust tumor growth inhibition in TMD8 and Mino xenograft mouse model. Doses as low as 3 mg/kg demonstrates a significant inhibitory effect. Conclusion: In summary, HZ-Q1070 is a potent and highly selective BTK degrader against both BTK-WT and multiple BTK inhibitors-resistant mutations. In vivo, HZ-Q1070 exhibits excellent pharmacokinetic properties, BTK degradation activity and robust tumor growth inhibition in TMD8 and Mino mouse xenograft tumor model. These findings support further clinical development of HZ-Q1070 for the treatment of B cell malignancies. Citation Format: Xingguo Liu, Yubo Zhou, Yizhe Wu, Xiaomin Luo, Jiangfeng Xie, Xinxin Jin, Jia Li, Xinglu Zhou. Discovery and preclinical study of novel BTK degrader HZ-Q1070 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3450.